Abstract
Progranulin is a secreted growth factor that is active in tumorigenesis, wound repair, and inflammation. Haploinsufficiency of the human progranulin gene, GRN, causes frontotemporal dementia. Progranulins are composed of chains of cysteine-rich granulin modules. Modules may be released from progranulin by proteolysis as 6kDa granulin polypeptides. Both intact progranulin and some of the granulin polypeptides are biologically active. The granulin module occurs in certain plant proteases and progranulins are present in early diverging metazoan clades such as the sponges, indicating their ancient evolutionary origin. There is only one Grn gene in mammalian genomes. More gene-rich Grn families occur in teleost fish with between 3 and 6 members per species including short-form Grns that have no tetrapod counterparts. Our goals are to elucidate progranulin and granulin module evolution by investigating (i): the origins of metazoan progranulins (ii): the evolutionary relationships between the single Grn of tetrapods and the multiple Grn genes of fish (iii): the evolution of granulin module architectures of vertebrate progranulins (iv): the conservation of mammalian granulin polypeptide sequences and how the conserved granulin amino acid sequences map to the known three dimensional structures of granulin modules. We report that progranulin-like proteins are present in unicellular eukaryotes that are closely related to metazoa suggesting that progranulin is among the earliest extracellular regulatory proteins still employed by multicellular animals. From the genomes of the elephant shark and coelacanth we identified contemporary representatives of a precursor for short-from Grn genes of ray-finned fish that is lost in tetrapods. In vertebrate Grns pathways of exon duplication resulted in a conserved module architecture at the amino-terminus that is frequently accompanied by an unusual pattern of tandem nearly identical module repeats near the carboxyl-terminus. Polypeptide sequence conservation of mammalian granulin modules identified potential structure-activity relationships that may be informative in designing progranulin based therapeutics.
Highlights
IntroductionProgranulin (which is known as PC cell-derived growth factor, acrogranin, proepithelin, granulin-epithelin precursor or epithelial transforming growth factor) is a growth factor-like, immunomodulatory and neurotrophic extracellular regulatory protein
Progranulin is a growth factor-like, immunomodulatory and neurotrophic extracellular regulatory protein
This study focuses upon unanswered questions in the evolution and structure of progranulins and their granulin domains, notably (a): How are granulin module-containing proteins in unicellular eukaryotes related to the progranulins of multicellular animals? (b): What evolutionary pathways led to the multiple Grn genes of ray-finned fish as opposed to the single Grn gene of the tetrapod genomes? (c): How might the granulin module architectures of vertebrate
Summary
Progranulin (which is known as PC cell-derived growth factor, acrogranin, proepithelin, granulin-epithelin precursor or epithelial transforming growth factor) is a growth factor-like, immunomodulatory and neurotrophic extracellular regulatory protein. It is composed of tandem repeats of the granulin/epithelin module, a protein motif that is defined by a conserved pattern of 12 cysteine residues (Fig 1A) [1, 2]. In some instances progranulin is processed to liberate individual granulin modules as 6kDa peptides, called granulins (reviewed in [3]) Both the granulins and the intact progranulin have growth modulatory activity [2, 4]. The physiological roles of progranulin include wound repair [18, 26], the regulation of inflammation [26,27,28,29,30], angiogenesis [18, 31], bone growth [32], sexual differentiation of the hypothalamus [33] and early embryogenesis [34]
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